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CC BY-NC-ND 4.0 · Planta Medica International Open 2019; 6(02): e41-e49
DOI: 10.1055/a-1001-2378
Original Papers
Eigentümer und Copyright ©Georg Thieme Verlag KG 2019

Pharmacokinetic-Pharmacodynamic (PK-PD) Modeling of Effect of Naringenin and Its Surface Modified Nanocarriers on Associated and Core Behaviors of Autism Spectrum Disorders (ASD)

Ranjana Bhandari
1   Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Study, Panjab University, Chandigarh, India
,
Jyoti K. Paliwal
1   Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Study, Panjab University, Chandigarh, India
,
Anurag Kuhad
1   Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, UGC-Centre of Advanced Study, Panjab University, Chandigarh, India
› Author Affiliations
Further Information

Publication History

received 13 May 2019
revised 10 July 2019

accepted 18 August 2019

Publication Date:
01 October 2019 (online)

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Abstract

The pharmacokinetic and pharmacodynamic (PK-PD) model was developed to describe the relationship between plasma/brain concentration of naringenin and its nanocarriers with behavioral and biochemical alterations in a rat model of autism spectrum disorders (ASD). Behavioral parameters like sensorimotor dysfunction, hyperlocomotion, anxiety-like behavior, social interaction, and repetitive behavior were investigated by rotarod, actophotometer, open-field, reciprocal social interaction, and repetitive self-grooming test respectively. Naringenin was administered in doses (25, 50, and 100 mg/kg) and in the form of its uncoated and glutathione as well as tween 80–coated PLGA nanocarriers (25 mg/kg) thrice daily (8 hourly). Sigmoid Emax model was applied to study the relationship between the concentration of naringenin in plasma/brain and behavioral effects (in terms of sensorimotor dysfunction, locomotor activity, anxiety-like behavior, social interaction ability, repetitive behavior) as well as biochemical changes (plasma levels of TNF-α, MMP-9, and HSP-70, and Pgp at BBB). Model parameters such as Eo, Emax, and EC50 indicate that maximum effect occurred after administration of GSH-coated naringenin nanoparticles and the minimum effect occurred with the 25 mg/kg dose of unencapsulated naringenin. The R2 value of 0.99 and small Akaike information criterion indicate the goodness of fit of the model. The PK-PD modeling done by sigmoid Emax model showed a positive correlation between plasma/brain drug concentration and neuroinflammatory markers as well as behaviors consistent with the ASD phenotype.  

Key words

pharmacokinetic and pharmacodynamic (PK-PD) - autism spectrum disorders (ASD) - naringenin - glutathione - tween 80 - nanoparticles

Supplementary Material

    Supplementary Material for this article is available online at http://www.thieme-connect.de/products.
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